SR-BI and ApoE knockout animals and use thereof as models for atherosclerosis and heart attack

Abstract

Transgenic animals that do not express functional SR-BI and ApoE develop severe atherosclerosis, by age four weeks in transgenic mice. Moreover, these animals exhibit progressive heart block by age four weeks, and die by age nine weeks. Pathology shows extensive fibrosis of the heart and occlusion of coronary arteries. The occlusion appears to be due to clotting, since fat deposition is in the walls. These animals are good models for the following diseases, and for screening of drugs useful in the treatment and/or prevention of these disorders: cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, and stroke. In contrast to other known models for atherosclerosis, these animals do not have to be fed extreme diets for long periods before developing atherosclerosis. No other known model for heart attacks and stroke is known.

We claim:  
     
       1. A transgenic mouse having homozygous disruptions in the SR-BI and ApoE genes that inhibit expression of active SR-BI and Apo-E, wherein the mouse is characterized by atherosclerotic plaque in the aortic sinuses and progressive heart block at between five and seven weeks of age. 
     
     
       2. A method for screening for compounds having an effect on disorders selected from the group consisting of cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, stroke and diseases associated with abnormal cardiac structure or function or elevated cholesterol or lipoprotein levels comprising 
       administering the compound to a transgenic mouse having homozygous disruptions in the SR-BI and ApoE genes that inhibit expression of active SR-BI and Apo-E wherein the mouse develops atherosclerotic plaque in the aortic sinuses and progressive heart block at between five and seven weeks of age and  
       determining the effect of the compound on cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, stroke, diseases associated with abnormal cardiac structure or function or elevated cholesterol or lipoprotein levels in the transgenic mouse relative to control mice not treated with compound.  
     
     
       3. The method of  claim 2  wherein the mouse is an Apo E knockout mouse. 
     
     
       4. The method of  claim 2  wherein the mouse does not express SR-BI. 
     
     
       5. The method of  claim 2  wherein the mouse does not express active SR-BI. 
     
     
       6. The method of  claim 3  wherein the mouse is an SR-BI and Apo E knockout. 
     
     
       7. The method of  claim 2  wherein the transgenic mouse is treated with a compound which lowers the level of SR-BI. 
     
     
       8. The method of  claim 2  wherein the transgenic mouse is treated with a compound which lowers the level of apolipoprotein E. 
     
     
       9. The method of  claim 2  wherein the mouse is screened for alterations in levels of cholesterol or lipoproteins.